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WO2021023194A1 - Crystal forms c and e of pyrazin-2(1h)-one compound and preparation method therefor - Google Patents

Crystal forms c and e of pyrazin-2(1h)-one compound and preparation method therefor Download PDF

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Publication number
WO2021023194A1
WO2021023194A1 PCT/CN2020/106896 CN2020106896W WO2021023194A1 WO 2021023194 A1 WO2021023194 A1 WO 2021023194A1 CN 2020106896 W CN2020106896 W CN 2020106896W WO 2021023194 A1 WO2021023194 A1 WO 2021023194A1
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crystal form
compound
formula
angles
ray powder
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PCT/CN2020/106896
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French (fr)
Chinese (zh)
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洪绯
黄进明
高龙辉
王世聪
殷婷婷
付志飞
罗妙荣
张杨
黎健
陈曙辉
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漳州片仔癀药业股份有限公司
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Priority to ES20850874T priority Critical patent/ES2960702T3/en
Priority to US17/633,319 priority patent/US11680061B2/en
Priority to CN202080054562.8A priority patent/CN114174271B/en
Priority to JP2022507752A priority patent/JP7198387B2/en
Priority to EP20850874.7A priority patent/EP4011867B1/en
Publication of WO2021023194A1 publication Critical patent/WO2021023194A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a crystal form of a pyrazine-2(1H)-one compound and a preparation method thereof, in particular to a preparation method of a compound of formula (II) and a crystal form thereof.
  • Fibroblast growth factor receptor is a receptor for fibroblast growth factor (FGF) signal transduction. Its family consists of four members (FGFR1, FGFR2, FGFR3, FGFR4), and is composed of extracellular immunoglobulin ( Ig)-like domain, hydrophobic transmembrane domain and intracellular part including tyrosine kinase domain. Fibroblast growth factor (FGF) through these receptors (FGFR) plays an important role in many physiological regulation processes such as cell proliferation, cell differentiation, cell migration and angiogenesis.
  • FGF fibroblast growth factor
  • FGF signaling pathway high expression, gene amplification, gene mutation, chromosomal reorganization, etc.
  • pathological processes such as tumor cell proliferation, migration, invasion and angiogenesis. Therefore, FGFR has become an important therapeutic target, attracting extensive research and development interest.
  • the present invention provides the hydrochloride of a compound of formula (I)
  • the structure of the hydrochloride salt of the compound of formula (I) is as shown in formula (III), wherein n is selected from 0.6-2.
  • n is selected from 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.
  • n is selected from 0.9, 1 and 1.1.
  • the present invention provides crystal form C of the compound of formula (II), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.24 ⁇ 0.20°, 9.58 ⁇ 0.20°, 10.45 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form C of the compound of formula (II) has characteristic diffraction peaks at the following 2 ⁇ angles: 5.24 ⁇ 0.20°, 9.58 ⁇ 0.20°, 10.45 ⁇ 0.20°, 14.25 ⁇ 0.20°, 20.86 ⁇ 0.20°, 24.99 ⁇ 0.20°, 26.21 ⁇ 0.20°, 27.71 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form C of the compound of formula (II) has characteristic diffraction peaks at the following 2 ⁇ angles: 5.24 ⁇ 0.20°, 9.58 ⁇ 0.20°, 10.45 ⁇ 0.20°, 14.26 ⁇ 0.20°, 20.86 ⁇ 0.20°, 24.99 ⁇ 0.20°, 26.21 ⁇ 0.20°, 27.71 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form C of the compound of formula (II) has characteristic diffraction peaks at the following 2 ⁇ angles: 5.24°, 8.45°, 9.08°, 9.58°, 10.45°, 11.49 °, 13.23°, 14.02°, 14.26°, 15.18°, 15.60°, 16.35°, 18.15°, 18.74°, 19.52°, 19.94°, 20.86°, 21.65°, 21.97°, 22.50°, 23.28°, 23.64°, 24.16°, 24.99°, 26.21°, 26.98°, 27.71°, 28.52°, 29.07°, 29.43°, 30.37°, 31.72°, 32.30°, 33.11°, 34.79°, 36.78°.
  • the XRPD pattern of the crystal form C of the compound of formula (II) is shown in FIG. 1.
  • the XRPD pattern analysis data of the crystal form C of the compound of formula (II) is shown in Table 1.
  • the crystalline form C of the compound of formula (II) above has a differential scanning calorimetry curve with an onset of an endothermic peak at 216.4°C ⁇ 2.0°C and an endothermic peak at 258.8°C ⁇ 2.0°C The starting point of the peak.
  • the DSC chart of the crystal form C of the compound of formula (II) is shown in FIG. 2.
  • thermogravimetric analysis curve of the crystal form C of the compound of formula (II) has a weight loss of 0.1380% at 118.6°C ⁇ 3.0°C, a weight loss of 6.7760% at 205.5°C ⁇ 3.0°C, and a weight loss of 6.7760% at 253.02°C ⁇ The weight loss reached 9.2750% at 3.0°C.
  • the crystal form C of the compound of formula (II) above has a TGA pattern as shown in FIG. 3.
  • the present invention provides the E crystal form of the compound of formula (II), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.05 ⁇ 0.20°, 10.36 ⁇ 0.20°, 14.66 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the E crystal form of the compound of formula (II) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.05 ⁇ 0.20°, 10.36 ⁇ 0.20°, 14.66 ⁇ 0.20°, 15.75 ⁇ 0.20°, 16.74 ⁇ 0.20°, 18.54 ⁇ 0.20°, 19.01 ⁇ 0.20°, 20.78 ⁇ 0.20°, 25.20 ⁇ 0.20°, 26.65 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the E crystal form of the compound of formula (II) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.05 ⁇ 0.20°, 10.36 ⁇ 0.20°, 14.66 ⁇ 0.20°, 15.75 ⁇ 0.20°, 16.74 ⁇ 0.20°, 18.54 ⁇ 0.20°, 25.20 ⁇ 0.20°, 26.65 ⁇ 0.20°, 27.28 ⁇ 0.20°, 27.94 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the E crystal form of the compound of formula (II) has characteristic diffraction peaks at the following 2 ⁇ angles: 5.52°, 9.05°, 10.36°, 11.09°, 13.94°, 14.66 °, 15.75°, 16.74°, 18.13°, 18.54°, 19.01°, 20.78°, 21.57°, 21.98°, 23.58°, 24.46°, 25.20°, 25.44°, 26.26°, 26.65°, 27.28°, 27.51°, 27.94°, 28.94°, 29.54°, 31.19°, 32.08°, 33.24°, 35.47°, 36.23°, 38.35°, 39.34°.
  • the XRPD pattern of the crystal form E of the compound of formula (II) is shown in FIG. 4.
  • the XRPD pattern analysis data of the crystal form E of the compound of formula (II) is shown in Table 2.
  • the crystalline form E of the compound of formula (II) above has a differential scanning calorimetry curve with the starting point of the endothermic peak at 261.8°C ⁇ 2.0°C.
  • the DSC spectrum of the crystal form E of the compound of formula (II) is shown in FIG. 5.
  • thermogravimetric analysis curve of the E crystal form of the compound of formula (II) at 150.0°C ⁇ 3.0°C has a weight loss of 1.72%, and a weight loss of 8.34% at 230.0°C ⁇ 3.0°C, and a weight loss of 8.34% at 280.0°C ⁇ The weight loss reached 9.41% at 3.0°C.
  • the crystal form E of the compound of formula (II) above has a TGA pattern as shown in FIG. 6.
  • the present invention also provides the use of the compound of the above formula (III), the compound of the above formula (II), the above crystal form C, and the above crystal form E in the preparation of drugs for the treatment of diseases related to FGFR.
  • the crystal form of compound E of formula (II) has good stability and is easy to prepare medicines. According to the experimental examples of trifluoroacetate salt of compound of formula (I), it can be seen that the crystal form of compound E of formula (II) has better performance against wild-type FGFR. Inhibitory activity, and the selectivity of FGFR2, 3 to FGFR1, 4 is higher. The mouse pharmacokinetic index of the crystal form E of compound of formula (II) is good.
  • the crystal form of compound C of formula (II) has good stability and is easy to prepare medicine. According to the experimental example of trifluoroacetate salt of compound of formula (I), it can be known that compound C of formula (II) has crystal form. Both showed good inhibitory activity to wild-type FGFR, and FGFR2 and 3 had higher selectivity to FGFR1 and 4.
  • the pharmacokinetic index of the crystal salt of compound C of formula (II) in mice is good.
  • the trifluoroacetate salt of the compound of formula (I) shows good inhibitory activity against wild-type FGFR, and FGFR2, 3 has high selectivity to FGFR1, 4.
  • the trifluoroacetate salt of the compound of formula (I) has a good pharmacokinetic index in mice.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • eq stands for equivalent or equivalent
  • PE petroleum ether
  • DMSO dimethyl sulfoxide
  • MeOH stands for methanol
  • TFA trifluoroacetic acid
  • the solvent used in the present invention can be obtained commercially, and the commercially available compound adopts the supplier's catalog name.
  • the solvents can be mixed first and then added to the reaction solution; or each single solvent can be added to the reaction solution in sequence and mixed in the reaction system.
  • Light tube voltage 40kV
  • light tube current 40mA
  • the method is: 25°C-300 or 350°C, 10°C/min.
  • Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test conditions Take samples (10-15mg) and place them in the DVS sample pan for testing.
  • Hygroscopicity classification ⁇ W% deliquescence Absorb enough water to form a liquid Very hygroscopic ⁇ W% ⁇ 15% Hygroscopic 15%> ⁇ W% ⁇ 2% Slightly hygroscopic 2%> ⁇ W% ⁇ 0.2%
  • ⁇ W% means the moisture gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of the crystal form C of compound of formula (II).
  • Figure 2 is a DSC chart of the crystal form of compound C of formula (II).
  • Figure 3 is a TGA spectrum of the crystal form of compound C of formula (II).
  • Figure 4 is an XRPD spectrum of Cu-K ⁇ radiation of the E crystal form of compound of formula (II).
  • Figure 5 is a DSC chart of the crystal form of compound E of formula (II).
  • Figure 6 is the TGA spectrum of the crystal form E of compound of formula (II).
  • Figure 7 is a DVS spectrum of the crystal form of compound C of formula (II).
  • Figure 8 is a DVS spectrum of the crystal form E of compound of formula (II).
  • compound BB-2-1 (2.0g, 18.77mmol, 2.17mL, 1eq, HCl) was dissolved in chlorobenzene (15.0mL), and compound BB-2-2 (8.3g , 65.69mmol, 5.8mL, 3.5eq), the mixture was slowly heated to 90°C and stirred for 16 hours.
  • Water (30.0 mL) and ethyl acetate (30.0 mL) were added to the reaction system, and the layers were separated while standing, while the aqueous phase was extracted three times with ethyl acetate (20.0 mL, 20.0 mL, 20.0 mL).
  • compound 4 250mg, 890.61 ⁇ mol, 1eq was dissolved in a mixed solvent of acetonitrile (20.0mL) and dichloromethane (5.0mL), and sulfonyl chloride (84mg, 623.43 ⁇ mol, 62.33 ⁇ L, 0.7 eq) in acetonitrile (2.5 mL), and the mixture was stirred at 0°C for 10 minutes.
  • Methanol 5.0 mL was added to the reaction solution to quench the reaction, and it was concentrated to dryness under reduced pressure.
  • the compound of formula (I) (44.4 g, 94.89 mmol, 1 eq) was dissolved in tetrahydrofuran (450 mL), and then an ethyl acetate solution of hydrogen chloride (4M, 94.89 mL, 4 eq) was added dropwise, and the mixture was stirred at 25° C. for 3 hrs. The reaction liquid was filtered to obtain a yellow solid, and the oil pump was pulled dry. The compound of formula (II) is obtained.
  • the moisture absorption and weight gain of the compound E crystal form of formula (II) at 25° C. and 80% RH is 0.5%, which is slightly hygroscopic.
  • the 33 P isotope-labeled kinase activity test (Reaction Biology Corp) was used to determine the IC 50 value to evaluate the inhibitory ability of the test compound on human FGFR1 and FGFR4.
  • Buffer conditions 20mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (Hepes) (pH 7.5), 10mM MgCl 2 , 1mM ethylene glycol-bis-(2-aminoethyl ether)tetraacetic acid (EGTA), 0.02% polyoxyethylene lauryl ether (Brij35), 0.02mg/mL bovine serum albumin (BSA), 0.1mM sodium vanadate (Na 3 VO 4 ), 2mM dithiothreitol (DTT), 1% DMSO.
  • test compound was dissolved in DMSO to prepare a 10 mM solution for use. Dissolve the substrate in the newly prepared buffer, add the test kinase to it and mix well. Using acoustic technology (Echo 550), the DMSO solution in which the test compound is dissolved is added to the above-mentioned mixed reaction solution.
  • the compound concentration in the reaction solution is 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 0.370 ⁇ M, 0.123 ⁇ M, 41.2nM, 13.7nM, 4.57nM, 1.52nM, 0.508nM, or 10 ⁇ M, 2.50 ⁇ M, 0.62 ⁇ M, 0.156 ⁇ M, 39.1nM , 9.8nM, 2.4nM, 0.61nM, 0.15nM, 0.038nM.
  • 33 P-ATP activity 0.01 ⁇ Ci/ ⁇ L, the corresponding concentration is listed in Table 3
  • FGFR1, FGFR4 and its substrate supplier product number, batch number, and concentration information in the reaction solution are listed in Table 3.
  • the reaction liquid was spotted on P81 ion exchange filter paper (Whatman#3698-915). After washing the filter paper repeatedly with 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured.
  • the kinase activity data is expressed by comparing the kinase activity of the test compound with the kinase activity of the blank group (only containing DMSO).
  • the IC 50 value is obtained by curve fitting using Prism4 software (GraphPad). The experimental results are shown in Table 4.
  • Table 3 Information about kinases, substrates and ATP in in vitro tests.
  • the trifluoroacetate salt of the compound of formula (I) exhibits good inhibitory activity against wild-type FGFR, and FGFR2, 3 have high selectivity to FGFR1, 4.
  • CD-1 mouse male
  • vehicle (0.5% (w/v) methylcellulose 0.5% (v/v) Tween 80 aqueous solution)
  • compound 0027 trifluoroacetate.
  • the solvent is 0.5% (w/v) methyl cellulose 0.5% (v/v) Tween 80 aqueous solution, and it is prepared according to the following procedure:
  • Animals in groups 1 and 2 were given 5 mg/mL and 30 mg/mL compound by single gavage, and the administration volume was 10 mL/kg.
  • the acceptable error of the collection time point is the time point within 1 hour of administration ⁇ 1 minute, and the other time point is the theoretical time ⁇ 5%.

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Abstract

A crystal form of a pyrazin-2(1H)-one compound and a preparation method therefor. The present invention specifically relates to a compound of formula (II) and a preparation method for a crystal form of the compound.

Description

吡嗪-2(1H)-酮类化合物的C晶型和E晶型及其制备方法Crystal form C and crystal form E of pyrazine-2(1H)-ketone compound and preparation method thereof
本申请主张如下优先权：This application claims the following priority:
CN201910731661.4，2019年8月8日；CN201910731661.4, August 8, 2019;
CN201911059969.5，2019年11月1日。CN201911059969.5, November 1, 2019.
技术领域Technical field
本发明涉及一种吡嗪-2(1H)-酮类化合物的晶型及其制备方法，具体涉及式(ⅠI)化合物及其晶型的制备方法。The invention relates to a crystal form of a pyrazine-2(1H)-one compound and a preparation method thereof, in particular to a preparation method of a compound of formula (II) and a crystal form thereof.
背景技术Background technique
成纤维细胞生长因子受体(FGFR)是成纤维细胞生长因子(FGF)信号传导的受体，其家族由四个成员(FGFR1、FGFR2、FGFR3、FGFR4)组成，为由细胞外免疫球蛋白(Ig)样结构域、疏水性跨膜区域和包括酪氨酸激酶区域的细胞内部分所组成的糖蛋白。成纤维细胞生长因子(FGF)通过这些受体(FGFR)在细胞增殖、细胞分化、细胞迁移和血管生成等许多生理学调节过程中发挥重要作用。有许多证据将FGF信号通路异常(高表达、基因扩增、基因突变、染色体重组等)与肿瘤细胞增殖、迁移、入侵和血管形成等许多病理过程直接相关联。因此，FGFR成为了一类重要治疗靶点，吸引了广泛的研发兴趣。Fibroblast growth factor receptor (FGFR) is a receptor for fibroblast growth factor (FGF) signal transduction. Its family consists of four members (FGFR1, FGFR2, FGFR3, FGFR4), and is composed of extracellular immunoglobulin ( Ig)-like domain, hydrophobic transmembrane domain and intracellular part including tyrosine kinase domain. Fibroblast growth factor (FGF) through these receptors (FGFR) plays an important role in many physiological regulation processes such as cell proliferation, cell differentiation, cell migration and angiogenesis. There are many evidences that the abnormality of FGF signaling pathway (high expression, gene amplification, gene mutation, chromosomal reorganization, etc.) is directly related to many pathological processes such as tumor cell proliferation, migration, invasion and angiogenesis. Therefore, FGFR has become an important therapeutic target, attracting extensive research and development interest.
发明内容Summary of the invention
本发明提供式(I)化合物的盐酸盐The present invention provides the hydrochloride of a compound of formula (I)
Figure PCTCN2020106896-appb-000001
Figure PCTCN2020106896-appb-000001
在本发明的一些方案中，上述式(I)化合物的盐酸盐，其结构如式(III)所示，其中，n选自0.6～2。In some embodiments of the present invention, the structure of the hydrochloride salt of the compound of formula (I) is as shown in formula (III), wherein n is selected from 0.6-2.
Figure PCTCN2020106896-appb-000002
Figure PCTCN2020106896-appb-000002
在本发明的一些方案中，上述n选自0.6、0.7、0.8、0.9、1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9和2。In some aspects of the present invention, the aforementioned n is selected from 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.
在本发明的一些方案中，上述n选自0.9、1和1.1。In some aspects of the present invention, the aforementioned n is selected from 0.9, 1 and 1.1.
在本发明的一些方案中，上述式(III)化合物结构如式(II)所示In some embodiments of the present invention, the structure of the compound of formula (III) is as shown in formula (II)
Figure PCTCN2020106896-appb-000003
Figure PCTCN2020106896-appb-000003
本发明提供式(II)化合物的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24±0.20°、9.58±0.20°、10.45±0.20°。The present invention provides crystal form C of the compound of formula (II), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.24±0.20°, 9.58±0.20°, 10.45±0.20°.
本发明的一些方案中，上述式(II)化合物的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24±0.20°、9.58±0.20°、10.45±0.20°、14.25±0.20°、20.86±0.20°、24.99±0.20°、26.21±0.20°、27.71±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form C of the compound of formula (II) has characteristic diffraction peaks at the following 2θ angles: 5.24±0.20°, 9.58±0.20°, 10.45±0.20°, 14.25 ±0.20°, 20.86±0.20°, 24.99±0.20°, 26.21±0.20°, 27.71±0.20°.
本发明的一些方案中，上述式(II)化合物的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24±0.20°、9.58±0.20°、10.45±0.20°、14.26±0.20°、20.86±0.20°、24.99±0.20°、26.21±0.20°、27.71±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the crystal form C of the compound of formula (II) has characteristic diffraction peaks at the following 2θ angles: 5.24±0.20°, 9.58±0.20°, 10.45±0.20°, 14.26 ±0.20°, 20.86±0.20°, 24.99±0.20°, 26.21±0.20°, 27.71±0.20°.
本发明的一些方案中，上述式(II)化合物的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24°、8.45°、9.08°、9.58°、10.45°、11.49°、13.23°、14.02°、14.26°、15.18°、15.60°、16.35°、18.15°、18.74°、19.52°、19.94°、20.86°、21.65°、21.97°、22.50°、23.28°、23.64°、24.16°、24.99°、26.21°、26.98°、27.71°、28.52°、29.07°、29.43°、30.37°、31.72°、32.30°、33.11°、34.79°、36.78°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form C of the compound of formula (II) has characteristic diffraction peaks at the following 2θ angles: 5.24°, 8.45°, 9.08°, 9.58°, 10.45°, 11.49 °, 13.23°, 14.02°, 14.26°, 15.18°, 15.60°, 16.35°, 18.15°, 18.74°, 19.52°, 19.94°, 20.86°, 21.65°, 21.97°, 22.50°, 23.28°, 23.64°, 24.16°, 24.99°, 26.21°, 26.98°, 27.71°, 28.52°, 29.07°, 29.43°, 30.37°, 31.72°, 32.30°, 33.11°, 34.79°, 36.78°.
本发明的一些方案中，上述式(II)化合物的C晶型，其XRPD图谱如图1所示。In some embodiments of the present invention, the XRPD pattern of the crystal form C of the compound of formula (II) is shown in FIG. 1.
本发明的一些方案中，上述式(II)化合物的C晶型，其XRPD图谱解析数据如表1所示。In some embodiments of the present invention, the XRPD pattern analysis data of the crystal form C of the compound of formula (II) is shown in Table 1.
表1：式(II)化合物的C晶型XRPD图谱解析数据Table 1: XRPD pattern analysis data of crystal form C of the compound of formula (II)
Figure PCTCN2020106896-appb-000004
Figure PCTCN2020106896-appb-000004
Figure PCTCN2020106896-appb-000005
Figure PCTCN2020106896-appb-000005
本发明的一些方案中，上述式(II)化合物的C晶型，其差示扫描量热曲线在216.4℃±2.0℃处具有吸热峰的起始点，在258.8℃±2.0℃处具有吸热峰的起始点。In some embodiments of the present invention, the crystalline form C of the compound of formula (II) above has a differential scanning calorimetry curve with an onset of an endothermic peak at 216.4°C±2.0°C and an endothermic peak at 258.8°C±2.0°C The starting point of the peak.
本发明的一些方案中，上述式(II)化合物的C晶型，其DSC图谱如图2所示。In some embodiments of the present invention, the DSC chart of the crystal form C of the compound of formula (II) is shown in FIG. 2.
本发明的一些方案中，上述式(II)化合物的C晶型，热重分析曲线在118.6℃±3.0℃处失重达0.1380％，在205.5℃±3.0℃处失重达6.7760％，在253.02℃±3.0℃处失重达9.2750％。In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form C of the compound of formula (II) has a weight loss of 0.1380% at 118.6℃±3.0℃, a weight loss of 6.7760% at 205.5℃±3.0℃, and a weight loss of 6.7760% at 253.02℃± The weight loss reached 9.2750% at 3.0℃.
本发明的一些方案中，上述式(II)化合物的C晶型，其TGA图谱如图3所示。In some embodiments of the present invention, the crystal form C of the compound of formula (II) above has a TGA pattern as shown in FIG. 3.
本发明提供了式(II)化合物的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.05±0.20°、10.36±0.20°、14.66±0.20°。The present invention provides the E crystal form of the compound of formula (II), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.05±0.20°, 10.36±0.20°, 14.66±0.20°.
本发明的一些方案中，上述式(II)化合物的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.05±0.20°、10.36±0.20°、14.66±0.20°、15.75±0.20°、16.74±0.20°、18.54±0.20°、19.01±0.20°、20.78±0.20°、25.20±0.20°、26.65±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the E crystal form of the compound of formula (II) has characteristic diffraction peaks at the following 2θ angles: 9.05±0.20°, 10.36±0.20°, 14.66±0.20°, 15.75 ±0.20°, 16.74±0.20°, 18.54±0.20°, 19.01±0.20°, 20.78±0.20°, 25.20±0.20°, 26.65±0.20°.
本发明的一些方案中，上述式(II)化合物的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.05±0.20°、10.36±0.20°、14.66±0.20°、15.75±0.20°、16.74±0.20°、18.54±0.20°、25.20±0.20°、26.65±0.20°、27.28±0.20°、27.94±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the E crystal form of the compound of formula (II) has characteristic diffraction peaks at the following 2θ angles: 9.05±0.20°, 10.36±0.20°, 14.66±0.20°, 15.75 ±0.20°, 16.74±0.20°, 18.54±0.20°, 25.20±0.20°, 26.65±0.20°, 27.28±0.20°, 27.94±0.20°.
本发明的一些方案中，上述式(II)化合物的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.52°、9.05°、10.36°、11.09°、13.94°、14.66°、15.75°、16.74°、18.13°、18.54°、19.01°、 20.78°、21.57°、21.98°、23.58°、24.46°、25.20°、25.44°、26.26°、26.65°、27.28°、27.51°、27.94°、28.94°、29.54°、31.19°、32.08°、33.24°、35.47°、36.23°、38.35°、39.34°。In some aspects of the present invention, the X-ray powder diffraction pattern of the E crystal form of the compound of formula (II) has characteristic diffraction peaks at the following 2θ angles: 5.52°, 9.05°, 10.36°, 11.09°, 13.94°, 14.66 °, 15.75°, 16.74°, 18.13°, 18.54°, 19.01°, 20.78°, 21.57°, 21.98°, 23.58°, 24.46°, 25.20°, 25.44°, 26.26°, 26.65°, 27.28°, 27.51°, 27.94°, 28.94°, 29.54°, 31.19°, 32.08°, 33.24°, 35.47°, 36.23°, 38.35°, 39.34°.
本发明的一些方案中，上述式(II)化合物的E晶型，其XRPD图谱如图4所示。In some embodiments of the present invention, the XRPD pattern of the crystal form E of the compound of formula (II) is shown in FIG. 4.
本发明的一些方案中，上述式(II)化合物的E晶型，其XRPD图谱解析数据如表2所示。In some embodiments of the present invention, the XRPD pattern analysis data of the crystal form E of the compound of formula (II) is shown in Table 2.
表2：式(II)化合物的E晶型XRPD图谱解析数据Table 2: XRPD pattern analysis data of crystal form E of the compound of formula (II)
Figure PCTCN2020106896-appb-000006
Figure PCTCN2020106896-appb-000006
本发明的一些方案中，上述式(II)化合物的E晶型，其差示扫描量热曲线在261.8℃±2.0℃处具有吸热峰的起始点。In some embodiments of the present invention, the crystalline form E of the compound of formula (II) above has a differential scanning calorimetry curve with the starting point of the endothermic peak at 261.8°C±2.0°C.
本发明的一些方案中，上述式(II)化合物的E晶型，其DSC图谱如图5所示。In some embodiments of the present invention, the DSC spectrum of the crystal form E of the compound of formula (II) is shown in FIG. 5.
本发明的一些方案中，上述式(II)化合物的E晶型，热重分析曲线在150.0℃±3.0℃处失重达1.72％，在230.0℃±3.0℃处失重达8.34％，在280.0℃±3.0℃处失重达9.41％。In some embodiments of the present invention, the thermogravimetric analysis curve of the E crystal form of the compound of formula (II) at 150.0℃±3.0℃ has a weight loss of 1.72%, and a weight loss of 8.34% at 230.0℃±3.0℃, and a weight loss of 8.34% at 280.0℃± The weight loss reached 9.41% at 3.0°C.
本发明的一些方案中，上述式(II)化合物的E晶型，其TGA图谱如图6所示。In some embodiments of the present invention, the crystal form E of the compound of formula (II) above has a TGA pattern as shown in FIG. 6.
本发明还提供了上述式(III)化合物、上述式(II)化合物、上述C晶型、上述E晶型在制备治疗与FGFR相关疾病的药物中的应用。The present invention also provides the use of the compound of the above formula (III), the compound of the above formula (II), the above crystal form C, and the above crystal form E in the preparation of drugs for the treatment of diseases related to FGFR.
技术效果Technical effect
式(II)化合物E晶型稳定性好，易于成药，根据式(I)化合物的三氟乙酸盐的实验例可知，式(II)化合物E晶型对野生型FGFR都展现出较好的抑制活性，且FGFR2、3对FGFR1、4的选择性较高。式(II)化合物E晶型小鼠药代动力学指标良好。The crystal form of compound E of formula (II) has good stability and is easy to prepare medicines. According to the experimental examples of trifluoroacetate salt of compound of formula (I), it can be seen that the crystal form of compound E of formula (II) has better performance against wild-type FGFR. Inhibitory activity, and the selectivity of FGFR2, 3 to FGFR1, 4 is higher. The mouse pharmacokinetic index of the crystal form E of compound of formula (II) is good.
式(II)化合物C晶型稳定性好，易于成药，根据式(I)化合物的三氟乙酸盐的实验例可知，式(II)化合物C晶型。对野生型FGFR都展现出较好的抑制活性，且FGFR2、3对FGFR1、4的选择性较高。The crystal form of compound C of formula (II) has good stability and is easy to prepare medicine. According to the experimental example of trifluoroacetate salt of compound of formula (I), it can be known that compound C of formula (II) has crystal form. Both showed good inhibitory activity to wild-type FGFR, and FGFR2 and 3 had higher selectivity to FGFR1 and 4.
式(II)化合物C晶型盐小鼠药代动力学指标良好。The pharmacokinetic index of the crystal salt of compound C of formula (II) in mice is good.
式(I)化合物的三氟乙酸盐对野生型FGFR都展现出较好的抑制活性，且FGFR2、3对FGFR1、4的选择性较高。式(I)化合物的三氟乙酸盐小鼠药代动力学指标良好。The trifluoroacetate salt of the compound of formula (I) shows good inhibitory activity against wild-type FGFR, and FGFR2, 3 has high selectivity to FGFR1, 4. The trifluoroacetate salt of the compound of formula (I) has a good pharmacokinetic index in mice.
定义和说明Definition and description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reaction in the specific embodiment of the present invention is completed in a suitable solvent, and the solvent must be suitable for the chemical change of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。Hereinafter, the present invention will be described in detail through examples, and these examples are not meant to limit the present invention in any way.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。All solvents used in the present invention are commercially available and can be used without further purification.
本发明采用下述缩略词：eq代表当量、等量；PE代表石油醚；DMSO代表二甲亚砜；MeOH代表甲醇；TFA代表三氟乙酸。The following abbreviations are used in the present invention: eq stands for equivalent or equivalent; PE stands for petroleum ether; DMSO stands for dimethyl sulfoxide; MeOH stands for methanol; TFA stands for trifluoroacetic acid.
本发明所使用的溶剂可经市售获得，市售化合物采用供应商目录名称。将混合溶剂加入到反应液中时，可以先将各个溶剂混合，然后加入到反应液中；或依次向反应液中加入各个单一溶剂，在反应体系中混合。The solvent used in the present invention can be obtained commercially, and the commercially available compound adopts the supplier's catalog name. When the mixed solvent is added to the reaction solution, the solvents can be mixed first and then added to the reaction solution; or each single solvent can be added to the reaction solution in sequence and mixed in the reaction system.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020106896-appb-000007
软件命名，市售化合物采用供应商目录名称。 Compounds are based on conventional naming principles in the field or used
Figure PCTCN2020106896-appb-000007
The software is named, and the commercially available compounds use the supplier catalog name.
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法Powder X-ray diffraction (X-ray powder diffractometer, XRPD) method of the present invention
大约10～20mg样品用于XRPD检测。Approximately 10-20 mg of sample is used for XRPD detection.
详细的XRPD参数如下：The detailed XRPD parameters are as follows:
光管：Cu,k2,
Figure PCTCN2020106896-appb-000008
Light pipe: Cu, k2,
Figure PCTCN2020106896-appb-000008
光管电压：40kV，光管电流：40mALight tube voltage: 40kV, light tube current: 40mA
发散狭缝：0.60mmDivergence slit: 0.60mm
探测器狭缝：10.50mmDetector slit: 10.50mm
防散射狭缝：7.10mmAnti-scatter slit: 7.10mm
扫描范围：4-40degScanning range: 4-40deg
步径：0.02degStep diameter: 0.02deg
步长：0.12秒Step length: 0.12 seconds
样品盘转速：15rpmSample plate speed: 15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法The differential thermal analysis (Differential Scanning Calorimeter, DSC) method of the present invention
取样品(0.5～1mg)置于DSC铝锅内进行测试，方法为：25℃–300或350℃，10℃/min。Take the sample (0.5～1mg) and put it in the DSC aluminum pot for testing, the method is: 25℃-300 or 350℃, 10℃/min.
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
取样品(2～5mg)置于TGA铂金锅内进行测试，在25mL/min N 2条件下，以10℃/min的升温速率，加热样品从室温到300度或失重20％。 Take the sample (2～5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/min N 2 and at a heating rate of 10℃/min, heat the sample from room temperature to 300°C or 20% weight loss.
本发明动态蒸汽吸附分析(Dynamic Vapor Sorption,DVS)方法The dynamic vapor adsorption analysis (Dynamic Vapor Sorption, DVS) method of the present invention
仪器型号：SMS DVS Advantage动态蒸汽吸附仪Instrument model: SMS DVS Advantage dynamic vapor adsorption instrument
测试条件：取样品(10～15mg)置于DVS样品盘内进行测试。Test conditions: Take samples (10-15mg) and place them in the DVS sample pan for testing.
详细的DVS参数如下：The detailed DVS parameters are as follows:
温度：25℃Temperature: 25℃
平衡：dm/dt＝0.01％/min(最短：10min，最长：180min)Balance: dm/dt=0.01%/min (shortest: 10min, longest: 180min)
干燥：0％RH下干燥120minDrying: 120min under 0%RH
RH(％)测试梯级：10％RH (%) test step: 10%
RH(％)测试梯级范围：0％-90％-0％RH(%) test step range: 0%-90%-0%
引湿性评价分类如下：The classification of hygroscopicity evaluation is as follows:
吸湿性分类Hygroscopicity classification ΔW％ΔW%
潮解deliquescence 吸收足量水分形成液体Absorb enough water to form a liquid
极具吸湿性Very hygroscopic ΔW％≥15％ΔW％≥15％
有吸湿性Hygroscopic 15％>ΔW％≥2％15%>ΔW%≥2%
略有吸湿性Slightly hygroscopic 2％>ΔW％≥0.2％2%>ΔW%≥0.2%
无或几乎无吸湿性No or almost no hygroscopicity ΔW％<0.2％ΔW%<0.2%
注：ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重。Note: ΔW% means the moisture gain of the test product at 25±1℃ and 80±2%RH.
附图说明Description of the drawings
图1为式(II)化合物C晶型的Cu-Kα辐射的XRPD谱图。Figure 1 is an XRPD spectrum of Cu-Kα radiation of the crystal form C of compound of formula (II).
图2为式(II)化合物C晶型的DSC谱图。Figure 2 is a DSC chart of the crystal form of compound C of formula (II).
图3为式(II)化合物C晶型的TGA谱图。Figure 3 is a TGA spectrum of the crystal form of compound C of formula (II).
图4为式(II)化合物E晶型的Cu-Kα辐射的XRPD谱图。Figure 4 is an XRPD spectrum of Cu-Kα radiation of the E crystal form of compound of formula (II).
图5为式(II)化合物E晶型的DSC谱图。Figure 5 is a DSC chart of the crystal form of compound E of formula (II).
图6为式(II)化合物E晶型的TGA谱图。Figure 6 is the TGA spectrum of the crystal form E of compound of formula (II).
图7为式(II)化合物C晶型的DVS谱图。Figure 7 is a DVS spectrum of the crystal form of compound C of formula (II).
图8为式(II)化合物E晶型的DVS谱图。Figure 8 is a DVS spectrum of the crystal form E of compound of formula (II).
具体实施方式detailed description
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail through the following examples, but it is not meant to limit the present invention in any way. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. It will be obvious.
实施例1：式(I)化合物及其三氟乙酸盐的制备Example 1: Preparation of compound of formula (I) and its trifluoroacetate salt
Figure PCTCN2020106896-appb-000009
Figure PCTCN2020106896-appb-000009
Figure PCTCN2020106896-appb-000010
Figure PCTCN2020106896-appb-000010
步骤1：化合物BB-1-3的合成Step 1: Synthesis of compound BB-1-3
将化合物BB-1-2(2.0g,11.49mmol,1eq)和化合物BB-1-1(2.6g,11.49mmol,1eq)溶解到水(6.0mL)和二氧六环(25.0mL)中，然后再加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(841mg,1.15mmol,0.1eq)和碳酸钾(4.8g,34.48mmol,3eq)，在氮气保护下加热至100℃反应16小时。将所得反应液抽滤旋干，粗品经柱层析(石油醚：乙酸乙酯＝1:0-0:1)纯化得到化合物BB-1-3。Dissolve compound BB-1-2 (2.0g, 11.49mmol, 1eq) and compound BB-1-1 (2.6g, 11.49mmol, 1eq) in water (6.0mL) and dioxane (25.0mL), Then add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (841mg, 1.15mmol, 0.1eq) and potassium carbonate (4.8g, 34.48mmol, 3eq), under nitrogen protection Heat to 100°C for 16 hours. The resulting reaction solution was filtered off with suction and spin-dried, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0-0:1) to obtain compound BB-1-3.
MS(ESI)m/z:190.0[M+H] +。 MS(ESI) m/z: 190.0 [M+H] + .
步骤2：化合物BB-1的合成Step 2: Synthesis of compound BB-1
将化合物BB-1-3(0.5g,2.64mmol,1eq)和吡啶(209mg,2.64mmol,213.28μL,1eq)加入到氯仿(20.0mL)中，冷却至0℃然后再加入溴素(422mg,2.64mmol,136.22μL,1eq)。在室温28℃下反应18小时。将反应物用硫代硫酸钠(1.0mL)淬灭，然后抽滤，将滤液浓缩，粗品使用快速硅胶柱层析法纯化(石油醚：乙酸乙酯＝1:0-1:1)。得到化合物BB-1。MS(ESI)m/z:267.9[M+H] +。 Compound BB-1-3 (0.5g, 2.64mmol, 1eq) and pyridine (209mg, 2.64mmol, 213.28μL, 1eq) were added to chloroform (20.0mL), cooled to 0 ℃ and then added bromine (422mg, 2.64mmol, 136.22μL, 1eq). React at room temperature 28°C for 18 hours. The reaction was quenched with sodium thiosulfate (1.0 mL), and then filtered with suction, the filtrate was concentrated, and the crude product was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:1). Compound BB-1 was obtained. MS (ESI) m/z: 267.9 [M+H] + .
1H NMR(400MHz,CD 3OD)δ:8.12(s,1H)7.90(s,1H)3.86(s,3H)2.43(s,3H)。 1 H NMR (400MHz, CD 3 OD) δ: 8.12 (s, 1H) 7.90 (s, 1H) 3.86 (s, 3H) 2.43 (s, 3H).
步骤3：化合物2的合成Step 3: Synthesis of compound 2
在氮气的保护下，将化合物BB-2-1(2.0g,18.77mmol,2.17mL,1eq,HCl)溶解到氯苯(15.0mL)中，25℃滴加化合物BB-2-2(8.3g,65.69mmol,5.8mL,3.5eq)，混合物在缓慢升温至90℃搅拌16小时。向反应体系中加入水(30.0mL)和乙酸乙酯(30.0mL)，静置分层，同时水相用乙酸乙酯(20.0mL，20.0mL，20.0mL)萃取三次。合并有机相，用饱和氯化钠溶液(30.0mL)洗涤一次，最后用无水硫酸钠干燥有机相，过滤并减压浓缩。粗品经柱层析(石油醚：乙酸乙酯＝1:0-2:1)分离纯化，得到化合物2。MS(ESI)m/z:178.7[M+1] +。 Under the protection of nitrogen, compound BB-2-1 (2.0g, 18.77mmol, 2.17mL, 1eq, HCl) was dissolved in chlorobenzene (15.0mL), and compound BB-2-2 (8.3g , 65.69mmol, 5.8mL, 3.5eq), the mixture was slowly heated to 90°C and stirred for 16 hours. Water (30.0 mL) and ethyl acetate (30.0 mL) were added to the reaction system, and the layers were separated while standing, while the aqueous phase was extracted three times with ethyl acetate (20.0 mL, 20.0 mL, 20.0 mL). The organic phases were combined, washed once with saturated sodium chloride solution (30.0 mL), and finally the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate=1:0-2:1) to obtain compound 2. MS(ESI) m/z: 178.7 [M+1] + .
1H NMR(400MHz,CDCl 3)δ:7.26(s,1H),3.61(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ: 7.26 (s, 1H), 3.61 (s, 3H).
步骤4：化合物4的合成Step 4: Synthesis of compound 4
在微波管中，在氮气的保护下，将化合物2(0.2g,1.12mmol,1eq)和化合物3(213mg,1.17mmol,1.05eq)溶解到二氧六环(1.5mL)和水(1.5mL)的混合溶液中，加入四三苯基磷钯(65mg,55.86μmol,0.05eq)、碳酸钠(130mg,1.23mmol,1.1eq)，混合物在120℃微波搅拌30分钟。直接浓缩反应液。粗品经柱层析(石油醚：乙酸乙酯＝1:0-0:1)(TLC检测石油醚：乙酸乙酯＝1:1)分离，得到化合物4。MS(ESI)m/z:281.0[M+1] +。 In a microwave tube, under the protection of nitrogen, compound 2 (0.2g, 1.12mmol, 1eq) and compound 3 (213mg, 1.17mmol, 1.05eq) were dissolved in dioxane (1.5mL) and water (1.5mL) To the mixed solution of ), palladium tetrakistriphenylphosphorus (65 mg, 55.86 μmol, 0.05 eq) and sodium carbonate (130 mg, 1.23 mmol, 1.1 eq) were added, and the mixture was stirred in microwave at 120° C. for 30 minutes. The reaction solution was directly concentrated. The crude product was separated by column chromatography (petroleum ether: ethyl acetate=1:0-0:1) (Petroleum ether: ethyl acetate=1:1 detected by TLC) to obtain compound 4. MS(ESI) m/z: 281.0 [M+1] + .
1H NMR(400MHz,CDCl 3)δ:7.64(d,2H),7.28(s,1H),6.59(t,1H),3.86(s,6H),3.61(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ: 7.64 (d, 2H), 7.28 (s, 1H), 6.59 (t, 1H), 3.86 (s, 6H), 3.61 (s, 3H).
步骤5：化合物0027-1的合成Step 5: Synthesis of compound 0027-1
在氮气的保护下，将化合物4(250mg,890.61μmol,1eq)溶解到乙腈(20.0mL)和二氯甲烷(5.0mL)的混合溶剂中，0℃缓慢滴加磺酰氯(84mg,623.43μmol,62.33μL,0.7eq)的乙腈(2.5mL)溶液，混合物在0℃搅拌10分钟。向反应液中加入甲醇(5.0mL)淬灭反应，并减压浓缩干。粗品经柱层析(石油醚：乙酸乙酯＝1:0-1:1)(TLC检测石油醚：乙酸乙酯＝1:1)分离，得到化合物0027-1。MS(ESI)m/z:314.9[M+H] +。 Under the protection of nitrogen, compound 4 (250mg, 890.61μmol, 1eq) was dissolved in a mixed solvent of acetonitrile (20.0mL) and dichloromethane (5.0mL), and sulfonyl chloride (84mg, 623.43μmol, 62.33 μL, 0.7 eq) in acetonitrile (2.5 mL), and the mixture was stirred at 0°C for 10 minutes. Methanol (5.0 mL) was added to the reaction solution to quench the reaction, and it was concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 1:0-1:1) (Petroleum ether: ethyl acetate = 1:1 detected by TLC) to obtain compound 0027-1. MS (ESI) m/z: 314.9 [M+H] + .
步骤6：式(I)化合物的合成Step 6: Synthesis of compound of formula (I)
在三口瓶中，将化合物0027-1(59mg,186.49μmol,1eq),双联嚬哪醇硼酸酯(52mg,205.14μmol,1.1eq)，醋酸钯(5mg,20.51μmol,0.11eq)和2-二环己基磷-2,4,6-三异丙基联苯(20mg,41.03μmol,0.22eq)，乙酸钾(60mg,615.42μmol,3.3eq)加入到二氧六环(4.0mL)溶液中，用氮气置换反应体系中的空气，并在氮气的饱和下，升温至100℃回流搅拌30分钟，降至25℃，加入化合物BB-1(50mg,186.49μmol,1eq)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯的二氯甲烷络合物(15mg,18.65μmol,0.1eq)，碳酸钾(77mg,559.47μmol,3eq)，二氧六环(4.0mL)和水(2.0mL)，用氮气置换反应体系中的空气，并在氮气的饱和下，升温至100℃回流搅拌8小时。直接浓缩反应液。将得到的粗品，用高效液相色谱分离纯化(色谱柱:Boston Green ODS150×30mm 5μm；流动相:[水(0.1％TFA)-ACN]；B％:30％-60％,8min)得到式(I)化合物的三氟乙酸盐。MS(ESI)m/z:468.2[M+H] +。 1H NMR(400MHz,CD 3OD)δ:8.79(s,1H),8.09(m,2H),6.76(m,2H),3.93(s,3H),3.89(s,3H),3.84(s,3H),3.80(s,3H),2.54(s,3H)。该盐溶于二氯甲烷，加饱和碳酸钠洗，有机相用无水硫酸钠干燥，过滤，滤液旋干得式(I)化合物。 1H NMR(400MHz,CDCl 3)δ:8.51(s,1H),8.15(s,1H),6.71(d,J＝2.8Hz,1H),6.63(d,J＝2.8Hz,1H),6.43(brs,2H),3.94(s,3H),3.92(s,3H),3.84(s,3H),3.79(s,3H),2.55(s,3H)。 In a three-necked flask, compound 0027-1 (59mg, 186.49μmol, 1eq), double lanalol borate (52mg, 205.14μmol, 1.1eq), palladium acetate (5mg, 20.51μmol, 0.11eq) and 2 -Dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (20mg, 41.03μmol, 0.22eq), potassium acetate (60mg, 615.42μmol, 3.3eq) was added to the dioxane (4.0mL) solution In, the air in the reaction system was replaced with nitrogen, and under the saturation of nitrogen, the temperature was raised to 100°C under reflux and stirred for 30 minutes, and then reduced to 25°C. Compound BB-1 (50mg, 186.49μmol, 1eq) was added, [1,1 '-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (15mg, 18.65μmol, 0.1eq), potassium carbonate (77mg, 559.47μmol, 3eq), dioxane (4.0 mL) and water (2.0 mL), the air in the reaction system was replaced with nitrogen, and under the saturation of nitrogen, the temperature was raised to 100° C. and reflux stirred for 8 hours. The reaction solution was directly concentrated. The crude product obtained was separated and purified by high performance liquid chromatography (column: Boston Green ODS150×30mm 5μm; mobile phase: [water (0.1%TFA)-ACN]; B%: 30%-60%, 8min) to obtain the formula (I) The trifluoroacetate salt of the compound. MS (ESI) m/z: 468.2 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ: 8.79 (s, 1H), 8.09 (m, 2H), 6.76 (m, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.84 (s) , 3H), 3.80 (s, 3H), 2.54 (s, 3H). The salt is dissolved in dichloromethane, washed with saturated sodium carbonate, the organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is spin-dried to obtain the compound of formula (I). 1 H NMR (400MHz, CDCl 3 ) δ: 8.51 (s, 1H), 8.15 (s, 1H), 6.71 (d, J = 2.8 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 6.43 (brs, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 2.55 (s, 3H).
实施例2：式(II)化合物的制备Example 2: Preparation of compound of formula (II)
Figure PCTCN2020106896-appb-000011
Figure PCTCN2020106896-appb-000011
将式(I)化合物(44.4g,94.89mmol,1eq)溶于四氢呋喃(450mL)中，随后滴加氯化氢(4M,94.89mL,4eq)的乙酸乙酯溶液，在25℃搅拌3hrs。将反应液过滤得黄色固体，油泵拉干。得式(II)化合物。 1H NMR(400MHz,DMSO-d 6)δ:8.71(s,1H),8.18(s,2H),6.82(d,J＝2.8Hz,1H),6.75(d,J＝2.8Hz,1H)3.91(s,3H),3.81(s,3H),3.80(s,3H),3.71(s,3H),2.44(s,3H). The compound of formula (I) (44.4 g, 94.89 mmol, 1 eq) was dissolved in tetrahydrofuran (450 mL), and then an ethyl acetate solution of hydrogen chloride (4M, 94.89 mL, 4 eq) was added dropwise, and the mixture was stirred at 25° C. for 3 hrs. The reaction liquid was filtered to obtain a yellow solid, and the oil pump was pulled dry. The compound of formula (II) is obtained. 1 H NMR (400MHz, DMSO-d 6 ) δ: 8.71 (s, 1H), 8.18 (s, 2H), 6.82 (d, J = 2.8 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H) 3.91(s, 3H), 3.81(s, 3H), 3.80(s, 3H), 3.71(s, 3H), 2.44(s, 3H).
实施例3：式(II)化合物的C晶型的制备Example 3: Preparation of Form C of Compound of Formula (II)
称取400mg的式(II)化合物加入40mL的玻璃瓶中，加入20mL的乙酸乙酯，搅拌使其成悬浊液。将上述样品置于磁力加热搅拌器上(50℃)进行搅拌60小时(避光)。样品快速离心将残留固体放入真空干燥箱，在45℃条件下真空干燥过夜去除残留溶剂得到固体1。称量大约50mg固体1于样品瓶中，加入1mL的乙醇溶剂，混悬液在50℃条件下持续搅拌48hrs后，离心后将残留固体放入真空干燥箱，在50℃条件下真空干燥过夜去除残留溶剂，得到式(II)化合物的C晶型。Weigh 400 mg of the compound of formula (II) into a 40 mL glass bottle, add 20 mL of ethyl acetate, and stir to make a suspension. The above sample was placed on a magnetic heating stirrer (50°C) and stirred for 60 hours (protected from light). The sample was quickly centrifuged, and the residual solid was put into a vacuum drying oven, and dried under vacuum at 45°C overnight to remove the residual solvent to obtain solid 1. Weigh approximately 50 mg of solid 1 into a sample bottle, add 1 mL of ethanol solvent, and stir the suspension for 48 hrs at 50°C. After centrifugation, put the residual solid in a vacuum drying oven, and vacuum dry at 50°C overnight to remove The solvent is left to obtain the crystal form C of the compound of formula (II).
实施例4：式(II)化合物的E晶型的制备Example 4: Preparation of E crystal form of compound of formula (II)
将乙醇6.6L加入到10L三口玻璃瓶中，并开始搅拌，将式(II)化合物330g加入到三口玻璃瓶中，升温至45℃，继续搅拌48小时。使用布氏漏斗抽滤，滤饼用乙醇200mL×2淋洗。收集滤饼并在真空干燥箱中50～55℃烘干14～20小时，得到式(II)化合物的E晶型。Add 6.6L of ethanol into a 10L three-necked glass bottle and start stirring, add 330g of the compound of formula (II) into the three-necked glass bottle, raise the temperature to 45°C, and continue stirring for 48 hours. Use a Buchner funnel for suction filtration, and rinse the filter cake with 200 mL×2 ethanol. The filter cake is collected and dried in a vacuum drying oven at 50-55° C. for 14-20 hours to obtain the E crystal form of the compound of formula (II).
实施例5：式(II)化合物C晶型的吸湿性研究Example 5: Study on the hygroscopicity of compound C of formula (II)
实验材料：Experimental Materials:
SMS DVS Advantage动态蒸汽吸附仪SMS DVS Advantage Dynamic Vapor Sorption Apparatus
实验方法：experimental method:
取式(II)化合物C晶型10～15mg置于DVS样品盘内进行测试。Take 10-15 mg of compound C crystal form of formula (II) and place it in the DVS sample pan for testing.
实验结果：Experimental results:
式(II)化合物C晶型的DVS谱图如图所示，△W＝1.1％。The DVS spectrum of the crystal form of compound C of formula (II) is shown in the figure, ΔW=1.1%.
实验结论：Experimental results:
式(II)化合物C晶型在25℃和80％RH下的吸湿增重为1.1％，略有吸湿性。The moisture absorption and weight gain of compound C of formula (II) at 25° C. and 80% RH is 1.1%, which is slightly hygroscopic.
实施例6：式(II)化合物E晶型的吸湿性研究Example 6: Study on Hygroscopicity of Compound E of Formula (II)
实验材料：Experimental Materials:
SMS DVS Advantage动态蒸汽吸附仪SMS DVS Advantage Dynamic Vapor Sorption Apparatus
实验方法：experimental method:
取式(II)化合物E晶型10～15mg置于DVS样品盘内进行测试。Take 10-15 mg of compound E crystal form of formula (II) and place it in the DVS sample pan for testing.
实验结果：Experimental results:
式(II)化合物E晶型的DVS谱图如图所示，△W＝0.5％。The DVS spectrum of the crystal form of compound E of formula (II) is shown in the figure, ΔW=0.5%.
实验结论：Experimental results:
式(II)化合物E晶型在25℃和80％RH下的吸湿增重为0.5％，略有吸湿性。The moisture absorption and weight gain of the compound E crystal form of formula (II) at 25° C. and 80% RH is 0.5%, which is slightly hygroscopic.
实验例1：野生型激酶体外抑制活性评价Experimental example 1: Evaluation of in vitro inhibitory activity of wild-type kinase
采用 33P同位素标记激酶活性测试(Reaction Biology Corp)测定IC 50值来评价受试化合物对人FGFR1、FGFR4的抑制能力。 The 33 P isotope-labeled kinase activity test (Reaction Biology Corp) was used to determine the IC 50 value to evaluate the inhibitory ability of the test compound on human FGFR1 and FGFR4.
缓冲液条件：20mM 4-(2-羟乙基)-1-哌嗪乙磺酸(Hepes)(pH 7.5),10mM MgCl 2,1mM乙二醇-双-(2-氨基乙醚)四乙酸(EGTA),0.02％聚氧乙烯月桂醚(Brij35),0.02mg/mL牛血清白蛋白(BSA),0.1mM钒酸钠(Na 3VO 4),2mM二硫苏糖醇(DTT),1％DMSO。 Buffer conditions: 20mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (Hepes) (pH 7.5), 10mM MgCl 2 , 1mM ethylene glycol-bis-(2-aminoethyl ether)tetraacetic acid ( EGTA), 0.02% polyoxyethylene lauryl ether (Brij35), 0.02mg/mL bovine serum albumin (BSA), 0.1mM sodium vanadate (Na 3 VO 4 ), 2mM dithiothreitol (DTT), 1% DMSO.
实验步骤：室温下，将受试化合物溶解在DMSO中配制成10mM溶液待用。将底物溶解在新配制的缓冲液中，向其中加入受测激酶并混合均匀。利用声学技术(Echo 550)将溶有受试化合物的DMSO溶液加入上述混匀的反应液中。反应液中化合物浓度为10μM,3.33μM,1.11μM,0.370μM,0.123μM,41.2nM,13.7nM,4.57nM,1.52nM,0.508nM，或为10μM,2.50μM,0.62μM,0.156μM,39.1nM,9.8nM,2.4nM,0.61nM,0.15nM,0.038nM。孵化15分钟后，加入 33P-ATP(活度0.01μCi/μL，相应浓度列在表3中)开始反应。FGFR1、FGFR4和其底物的供应商货号、批号以及在反应液中的浓度信息列在表3中。反应在室温下进行120分钟后，将反应液点在P81离子交换滤纸(Whatman#3698-915)上。用0.75％磷酸溶液反复清洗滤纸后，测定滤纸上残留的磷酸化底物的放射性。激酶活性数据用含有受试化合物的激酶活性和空白组(仅含有DMSO)的激酶活性的比对表示，通过Prism4软件(GraphPad)进行曲线拟合得到IC 50值，实验结果如表4所示。 Experimental procedure: At room temperature, the test compound was dissolved in DMSO to prepare a 10 mM solution for use. Dissolve the substrate in the newly prepared buffer, add the test kinase to it and mix well. Using acoustic technology (Echo 550), the DMSO solution in which the test compound is dissolved is added to the above-mentioned mixed reaction solution. The compound concentration in the reaction solution is 10μM, 3.33μM, 1.11μM, 0.370μM, 0.123μM, 41.2nM, 13.7nM, 4.57nM, 1.52nM, 0.508nM, or 10μM, 2.50μM, 0.62μM, 0.156μM, 39.1nM , 9.8nM, 2.4nM, 0.61nM, 0.15nM, 0.038nM. After 15 minutes of incubation, 33 P-ATP (activity 0.01μCi/μL, the corresponding concentration is listed in Table 3) was added to start the reaction. FGFR1, FGFR4 and its substrate supplier product number, batch number, and concentration information in the reaction solution are listed in Table 3. After the reaction was carried out at room temperature for 120 minutes, the reaction liquid was spotted on P81 ion exchange filter paper (Whatman#3698-915). After washing the filter paper repeatedly with 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured. The kinase activity data is expressed by comparing the kinase activity of the test compound with the kinase activity of the blank group (only containing DMSO). The IC 50 value is obtained by curve fitting using Prism4 software (GraphPad). The experimental results are shown in Table 4.
表3：体外测试中激酶、底物和ATP的相关信息。Table 3: Information about kinases, substrates and ATP in in vitro tests.
激酶Kinase 供应商supplier Cat#Cat# Lot#Lot# ATP浓度(μM)ATP concentration (μM)
FGFR1FGFR1 Invitrogen Invitrogen PV3146PV3146 28427Q28427Q 55
FGFR2FGFR2 Invitrogen Invitrogen PV3368PV3368 31517I31517I 55
FGFR3FGFR3 Invitrogen Invitrogen PV3145PV3145 28459R28459R 3030
FGFR4FGFR4 InvitrogenInvitrogen P3054P3054 26967J26967J 2.52.5
底物Substrate 供应商supplier Cat#Cat# Lot#Lot# 反应液中底物浓Substrate concentration in the reaction solution
 To  To  To  To 度(μM)Degree (μM)
pEY(mg/ml)+MnpEY(mg/ml)+Mn SigmaSigma P7244-250MGP7244-250MG 062K5104V062K5104V 0.20.2
pEY(mg/ml)+MnpEY(mg/ml)+Mn SigmaSigma P7244-250MGP7244-250MG 062K5104V062K5104V 0.20.2
pEY(mg/ml)+MnpEY(mg/ml)+Mn SigmaSigma P7244-250MGP7244-250MG 062K5104V062K5104V 0.20.2
pEY(mg/ml)+MnpEY(mg/ml)+Mn SigmaSigma P7244-250MGP7244-250MG 062K5104V062K5104V 0.20.2
表4：本发明化合物体外筛选试验结果Table 4: In vitro screening test results of the compounds of the present invention
Figure PCTCN2020106896-appb-000012
Figure PCTCN2020106896-appb-000012
结论：式(I)化合物的三氟乙酸盐对野生型FGFR都展现出较好的抑制活性，且FGFR2、3对FGFR1、4的选择性较高。Conclusion: The trifluoroacetate salt of the compound of formula (I) exhibits good inhibitory activity against wild-type FGFR, and FGFR2, 3 have high selectivity to FGFR1, 4.
实验例2：化合物药代动力学评价Experimental example 2: Evaluation of compound pharmacokinetics
实验目的：测试化合物在小鼠体内药代动力学Experimental purpose: To test the pharmacokinetics of the compound in mice
实验材料：Experimental Materials:
CD-1小鼠(雄性)、溶媒(0.5％(w/v)甲基纤维素0.5％(v/v)吐温80水溶液)、化合物0027的三氟乙酸盐。CD-1 mouse (male), vehicle (0.5% (w/v) methylcellulose 0.5% (v/v) Tween 80 aqueous solution), compound 0027 trifluoroacetate.
1、给药制剂的配制：1. Preparation of administration preparation:
溶媒为0.5％(w/v)甲基纤维素0.5％(v/v)吐温80水溶液，并根据以下程序进行配制：The solvent is 0.5% (w/v) methyl cellulose 0.5% (v/v) Tween 80 aqueous solution, and it is prepared according to the following procedure:
a.加入约50％体积的纯化水于合适的容器中，并加热到约60℃至70℃。a. Add about 50% of the volume of purified water to a suitable container and heat to about 60°C to 70°C.
b.当水温到达指定值范围时，关掉加热器。缓慢加入所需量的甲基纤维素于上述容器中并不断搅拌。b. When the water temperature reaches the specified value range, turn off the heater. Slowly add the required amount of methyl cellulose to the above container with constant stirring.
c.4℃持续搅拌直到目测为澄清溶液。c. Continue stirring at 4°C until it is a clear solution visually.
d.加入所需体积吐温80至上述溶液中。持续搅拌至目测吐温80均匀分散，且为澄清溶液。d. Add the required volume of Tween 80 to the above solution. Continue to stir until the Tween 80 is evenly dispersed and is a clear solution.
e.用适量纯水将上述溶液定容到最终体积。e. Use an appropriate amount of pure water to dilute the above solution to the final volume.
f.持续搅拌直至均一溶液形成。f. Continue stirring until a homogeneous solution is formed.
灌胃给药制剂的配制：Preparation of oral administration preparations:
a.称取适量的供试品放入玻璃瓶内；a. Weigh an appropriate amount of test product into a glass bottle;
b.加入70％体积的溶媒(0.5％(w/v)甲基纤维素0.5％(v/v)吐温80水溶液)；b. Add 70% volume of solvent (0.5% (w/v) methyl cellulose 0.5% (v/v) Tween 80 aqueous solution);
c.搅拌制剂直至目视均一，需要的时候水浴超声；c. Stir the preparation until it is visually uniform, and water bath ultrasound when needed;
e.补足剩余体积的0.5％甲基纤维素+0.5％吐温80，搅拌均一。e. Make up the remaining volume of 0.5% methyl cellulose + 0.5% Tween 80, and stir uniformly.
2、给药2. Administration
第1、2组动物分别通过单次灌胃给予5mg/mL,30mg/mL的化合物，给药体积为10mL/kg。Animals in groups 1 and 2 were given 5 mg/mL and 30 mg/mL compound by single gavage, and the administration volume was 10 mL/kg.
在给药前称量动物体重，根据体重计算给药体积。Weigh the animals before administration, and calculate the administration volume based on the body weight.
3、样品采集和处理3. Sample collection and processing
通过隐静脉采血方式在规定的时间采集(0.25、0.5、1、2、4、6、8、24h)全血样品(30μL)，并在试验记录中记录实际采血时间。采集时间点可接受的误差为给药1小时内时间点±1分钟，其他时间点的为理论时间±5％。Collect a whole blood sample (30 μL) at the specified time (0.25, 0.5, 1, 2, 4, 6, 8, 24h) through saphenous vein blood collection, and record the actual blood collection time in the test record. The acceptable error of the collection time point is the time point within 1 hour of administration ± 1 minute, and the other time point is the theoretical time ± 5%.
所有血样立即转移至贴有标签的含K2-EDTA的商品化离心管中。血样采集后，4℃，3200转/分钟离心10分钟吸取上清血浆，迅速至于干冰中，保持-20℃或更低温度，用于LC-MS/MS分析。并计算药代参数，实验结果：见表5。All blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After the blood sample is collected, the supernatant plasma is collected by centrifugation at 3200 rpm for 10 minutes at 4°C, and quickly placed in dry ice, keeping the temperature at -20°C or lower for LC-MS/MS analysis. And calculate the pharmacokinetic parameters, the experimental results: see Table 5.
表5药代动力学测试结果Table 5 Pharmacokinetic test results
Figure PCTCN2020106896-appb-000013
Figure PCTCN2020106896-appb-000013
ND代表:未确定ND stands for: Not determined
结论：式(I)化合物的三氟乙酸盐小鼠药代动力学指标良好。Conclusion: The trifluoroacetate of the compound of formula (I) has good pharmacokinetic indexes in mice.

Claims (23)

  1. 式(I)化合物的盐酸盐Hydrochloride of compound of formula (I)
    Figure PCTCN2020106896-appb-100001
    Figure PCTCN2020106896-appb-100001
  2. 根据权利要求1所述的式(I)化合物的盐酸盐，其结构如式(III)所示The hydrochloride salt of the compound of formula (I) according to claim 1, and its structure is as shown in formula (III)
    Figure PCTCN2020106896-appb-100002
    Figure PCTCN2020106896-appb-100002
    其中，n选自0.6～2。Wherein, n is selected from 0.6-2.
  3. 根据权利要求2所述的盐酸盐，其中，n选自0.6、0.7、0.8、0.9、1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9和2。The hydrochloride salt according to claim 2, wherein n is selected from 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.
  4. 根据权利要求3所述的盐酸盐，其中，n选自0.9、1和1.1。The hydrochloride salt of claim 3, wherein n is selected from 0.9, 1 and 1.1.
  5. 根据权利要求4所述的盐酸盐，其结构如式(II)所示The hydrochloride according to claim 4, the structure of which is shown in formula (II)
    Figure PCTCN2020106896-appb-100003
    Figure PCTCN2020106896-appb-100003
  6. 根据权利要求3～5任意一项所述盐酸盐的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24±0.20°、9.58±0.20°、10.45±0.20°。The crystal form C of the hydrochloride according to any one of claims 3 to 5, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.24±0.20°, 9.58±0.20°, 10.45±0.20°.
  7. 根据权利要求6所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24±0.20°、9.58±0.20°、10.45±0.20°、14.26±0.20°、20.86±0.20°、24.99±0.20°、26.21±0.20°、27.71±0.20°。The crystal form C according to claim 6, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.24±0.20°, 9.58±0.20°, 10.45±0.20°, 14.26±0.20°, 20.86±0.20 °, 24.99±0.20°, 26.21±0.20°, 27.71±0.20°.
  8. 根据权利要求7所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24°、8.45°、9.08°、9.58°、10.45°、11.49°、13.23°、14.02°、14.26°、15.18°、15.60°、16.35°、18.15°、18.74°、19.52°、 19.94°、20.86°、21.65°、21.97°、22.50°、23.28°、23.64°、24.16°、24.99°、26.21°、26.98°、27.71°、28.52°、29.07°、29.43°、30.37°、31.72°、32.30°、33.11°、34.79°、36.78°。The crystal form C according to claim 7, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.24°, 8.45°, 9.08°, 9.58°, 10.45°, 11.49°, 13.23°, 14.02° , 14.26°, 15.18°, 15.60°, 16.35°, 18.15°, 18.74°, 19.52°, 19.94°, 20.86°, 21.65°, 21.97°, 22.50°, 23.28°, 23.64°, 24.16°, 24.99°, 26.21 °, 26.98°, 27.71°, 28.52°, 29.07°, 29.43°, 30.37°, 31.72°, 32.30°, 33.11°, 34.79°, 36.78°.
  9. 根据权利要求8所述的C晶型，其XRPD图谱如图1所示。The crystal form C according to claim 8, and its XRPD pattern is shown in Figure 1.
  10. 根据权利要求7～9任意一项所述的C晶型，其差示扫描量热曲线在216.4℃±2.0℃处具有吸热峰的起始点，在258.8℃±2.0℃处具有吸热峰的起始点。The crystal form C according to any one of claims 7-9, the differential scanning calorimetry curve has an endothermic peak starting point at 216.4℃±2.0℃, and an endothermic peak at 258.8℃±2.0℃ Starting point.
  11. 根据权利要求10所述的C晶型，其DSC图谱如图2所示。The crystal form C according to claim 10, and its DSC spectrum is shown in FIG. 2.
  12. 根据权利要求7～9任意一项所述的C晶型，热重分析曲线在118.6℃±3.0℃失重达0.1380％，在205.5℃±3.0℃失重达6.7760％，在253.02℃±3.0℃失重达9.2750％。According to the crystal form C of any one of claims 7-9, the thermogravimetric analysis curve has a weight loss of 0.1380% at 118.6℃±3.0℃, a weight loss of 6.7760% at 205.5℃±3.0℃, and a weight loss of 253.02℃±3.0℃. 9.2750%.
  13. 根据权利要求12所述的C晶型，其TGA图谱如图3所示。The crystal form C according to claim 12, whose TGA pattern is shown in FIG. 3.
  14. 根据权利要求3～5任意一项所述盐酸盐的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.05±0.20°、10.36±0.20°、14.66±0.20°。The crystal form E of the hydrochloride salt according to any one of claims 3 to 5, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.05±0.20°, 10.36±0.20°, 14.66±0.20°.
  15. 根据权利要求14所述的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.05±0.20°、10.36±0.20°、14.66±0.20°、15.75±0.20°、16.74±0.20°、18.54±0.20°、19.01±0.20°、20.78±0.20°、25.20±0.20°、26.65±0.20°。The crystal form E according to claim 14, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.05±0.20°, 10.36±0.20°, 14.66±0.20°, 15.75±0.20°, 16.74±0.20 °, 18.54±0.20°, 19.01±0.20°, 20.78±0.20°, 25.20±0.20°, 26.65±0.20°.
  16. 根据权利要求14所述的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.05±0.20°、10.36±0.20°、14.66±0.20°、15.75±0.20°、16.74±0.20°、18.54±0.20°、25.20±0.20°、26.65±0.20°、27.28±0.20°、27.94±0.20°。The crystal form E according to claim 14, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.05±0.20°, 10.36±0.20°, 14.66±0.20°, 15.75±0.20°, 16.74±0.20 °, 18.54±0.20°, 25.20±0.20°, 26.65±0.20°, 27.28±0.20°, 27.94±0.20°.
  17. 根据权利要求15或16所述的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.52°、9.05°、10.36°、11.09°、13.94°、14.66°、15.75°、16.74°、18.13°、18.54°、19.01°、20.78°、21.57°、21.98°、23.58°、24.46°、25.20°、25.44°、26.26°、26.65°、27.28°、27.51°、27.94°、28.94°、29.54°、31.19°、32.08°、33.24°、35.47°、36.23°、38.35°、39.34°。The crystal form E according to claim 15 or 16, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.52°, 9.05°, 10.36°, 11.09°, 13.94°, 14.66°, 15.75°, 16.74°, 18.13°, 18.54°, 19.01°, 20.78°, 21.57°, 21.98°, 23.58°, 24.46°, 25.20°, 25.44°, 26.26°, 26.65°, 27.28°, 27.51°, 27.94°, 28.94° , 29.54°, 31.19°, 32.08°, 33.24°, 35.47°, 36.23°, 38.35°, 39.34°.
  18. 根据权利要求17所述的E晶型，其XRPD图谱如图4所示。The crystal form E according to claim 17, whose XRPD pattern is shown in FIG. 4.
  19. 根据权利要求15～18任意一项所述的E晶型，其差示扫描量热曲线在261.8℃±2.0℃处具有吸热峰的起始点。The crystal form E according to any one of claims 15 to 18, whose differential scanning calorimetry curve has the starting point of the endothermic peak at 261.8°C±2.0°C.
  20. 根据权利要求19所述的E晶型，其DSC图谱如图5所示。The crystal form E according to claim 19, and its DSC spectrum is shown in Fig. 5.
  21. 根据权利要求15～18任意一项所述的E晶型，热重分析曲线在150.0℃±3.0℃失重达1.72％，在230.0℃±3.0℃失重达8.34％，在280.0℃±3.0℃失重达9.41％。According to the crystal form E of any one of claims 15-18, the thermogravimetric analysis curve has a weight loss of 1.72% at 150.0℃±3.0℃, a weight loss of 8.34% at 230.0℃±3.0℃, and a weight loss of 280.0℃±3.0℃. 9.41%.
  22. 根据权利要求21所述的E晶型，其TGA图谱如图6所示。The crystal form E according to claim 21, whose TGA pattern is shown in FIG. 6.
  23. 根据权利要求1～5任意一项盐酸盐、权利要求6～13任意一项所述的C晶型、权利要求14～22任意一项所述的E晶型在制备治疗与FGFR相关疾病的药物中的应用。According to the hydrochloride salt of any one of claims 1 to 5, the crystal form C of any one of claims 6 to 13, and the crystal form E of any one of claims 14 to 22 are used in the preparation of treatments for FGFR-related diseases Application in medicine.
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